The normal cell in normal tissue is confined to a narrow range of function and structure regulated by its differentiation state, genetic program of metabolism, tissue specialization, by constraints induced by neighboring cells, the extracellular matrix and availability of exogenous factors and metabolic substrates. Cells are able to handle normal physiological demands (homeostasis) or adapt to excessive physiological stresses and pathological stimuli by altering their steady state to preserve cell viability and function. If the adaptive responses to stimuli are exceeded, then a sequence of cellular events follow that transform normal cells to injured or diseased cells in an attempt to remodel local tissue. This process can lead to a number of diseases driven by enhanced cell proliferation, migration and invasion, production of matrix metalloproteinases, infiltration of inflammatory cells, tissue destruction and dysfunctional tissue remodeling. Regardless of the etiology, such disease processes are commonly found in inflammatory diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel diseases, diabetes), proliferative diseases (such as cancer and metastases), degenerative diseases (such as osteoarthritis, osteoporosis, Alzheimer's, Parkinson's) and injuries caused by wounds or bums.
Current medical approaches to treat or prevent such diseases typically involve the use of reagents that attempt to block mechanisms affecting cell proliferation, cell migration, or the production of enzymes or growth factors. However, because such reagents are not specific to diseased cells and current practices do not yet allow targeting of these reagents specifically to sites of disease, such a therapeutic approach is typically toxic to the host if used for any length of time or at high dosages as may be required to treat or prevent the disease. This toxicity of current reagents is a severe limitation to the efficacy of current medical treatments.
The response-to-injury processes involving cytokines/growth factors and matrix degrading enzymes controlling response-to-injury processes, are regulated by a common transcription factor, activating protein-1 (AP-1). When injury occurs, the initial stage involves a transient increase in the production of hyaluronic acid (HA) which is accompanied by an increase in HA receptors such as RHAMM (Receptor Hyaluronic Acid Mediated Motility). The RHAMM molecule serves as a specific target on the cell that is required for the activation of the AP-1 pathway. Molecules that regulate transient cellular phases, such as RHAMM, make excellent therapeutic targets since these molecules are only transiently expressed in diseased tissue. The transient expression pattern provides tissue specificity and low toxicity to the human body.
Thus there is a need to provide peptides that act as therapeutic agents on a variety of cells responding to injury or disease by inhibiting activation of signaling pathways leading to AP-1 activation. Further there is a need to provide antibodies that act as therapeutic agents on a variety of cells responding to injury or disease by inhibiting activation of signaling pathways leading to AP-1 activation. Further still, there is a need to provide vaccines that prevent, ameliorate or treat injury or disease by inhibiting activation of signaling pathways leading to AP-1 activation.
The present invention discloses a sequence of cellular transition states that are involved in the transformation of normal cells to diseased cells that is characteristic to all cell types, and thus, all tissues. Transitory molecules produced during the early phases of disease which are responsible for the transition of cells from normal to diseased state are described, as well as the use of such molecules in the diagnosis, treatment and/or prevention of a wide variety of diseases is provided.